Conopeptides are bioactive peptides isolated from marine cone snail venom. Many of these small, conformationally constrained peptides function as potent and selective ion channel modulators. Conopeptides that block nicotinic acetylcholine receptors (nAChRs) have been isolated, and some are known to specifically modulate the activity of neuronal nAChR subtypes. Presynaptic neuronal nAChRs function to modulate the release of a variety of neurotransmitters, including dopamine, glutamate, GABA and acetylcholine. Compounds that selectively modulate the activity of neuronal nicotinic subtypes may have therapeutic utility in treating a variety of diseases impacting mental health, such as schizophrenia, Alzheimer's disease, attention deficit/hyperactivity disorder, and depression. We propose to develop methods for the efficient discovery of novel conopeptides active at neuronal nAChRs, and to characterize these peptides ability to selectively modulate neurotransmitter release. Conopeptides active at nAChRs are hypervariable in sequence, yet have a conserved structural framework and are encoded by related genes. Methods for the rapid genomic isolation of conopeptide genes will be developed and used to survey Cone species for novel nAChR-active peptides. In Phase II of this proposal, conopeptides with potent and selective activity at neuronal nACHRs will be characterized in terms of their ability to selectively modulate neurotransmitter release. PROPOSED COMMERCIAL APPLICATIONS: Therapeutic compounds acting at neuronal nicotinic receptors to modulate neurotransmitter release may be of benefit in a variety of diseases in which mental health is negatively impacted. A number of companies have established programs to develop small-molecule nicotinic modulators for Alzheimer's, Parkinson's, dementia and chronic pain. Potent and selective conopeptide nAChR ligands could themselves serve as therapeutics, or could be used in a small-molecule development program.